In the first controlled, double-blind study of NAC in that population, one-year survival with the drug was 73%, compared with 82% with placebo (P=0.20), Robert Squires, MD, of Children's Hospital of Pittsburgh, reported here at Digestive Disease Week.

Transplant-free survival was even worse at 35%, compared with 53% for the placebo group (P=0.03), Squires said.

"Our results do not support the broad use of NAC in nonacetaminophen acute liver failure in children," Squires told attendees.

Squires said the results were somewhat surprising because an earlier trial in adults had shown that NAC improved survival, with a transplant-free survival rate of 40% after three weeks compared with 27% in a placebo group.

He said the findings highlight the importance of testing drugs intended for children in children, "regardless of results in adults."

Acute liver failure unrelated to acetaminophen is rare -- a major children's hospital might see five to 10 cases a year, Squires said -- but is "devastating" when it does occur.

Estimates are that 43% of children with the condition die or undergo liver transplant. Moreover, outcomes after transplant for pediatric acute liver failure are typically worse than when transplant is performed for other reasons.

Thus, Squires said, the pediatric study looked at one-year outcomes rather than the shorter follow-up used in the adult trial.

The trial was conducted at 24 sites from 2003 to 2009, mainly in the U.S. but with three in Canada and Great Britain.

Children were excluded if they had previously received NAC or had sepsis, intractable hypotension, cancer, evidence of cerebral herniation, or were pregnant.

A total of 634 were screened, with 271 found eligible and 184 willing to participate. After randomization, two assigned to placebo withdrew.

Median age of participants was about 4, although one-quarter were 10 or older. About a third were younger than 2.

Participants received intravenous infusions of NAC at 150 mg/kg/day or placebo for up to seven days. Median time from admission to start of treatment was three days.

In more than half the cases, the cause of acute liver failure was unknown, which Squires said was typical in children with the condition. "Most of the time we never find a reason," he said at a press briefing on the study.

Among the causes that were known were autoimmune disease, metabolic problems, infections, and "other" such as hemophagocytic syndrome or drug reactions.

NAC appeared particularly unhelpful in younger patients. Among those younger than 2, transplant-free survival was 28% at one year with NAC versus 58% with placebo (P=0.03).

In older children, transplant-free survival rates were almost equal.

In fact, there were no subgroups for whom NAC showed even a hint of benefit, according to the analyses Squires presented. It was worse or no better than placebo for all encephalopathy grades, all levels of organ failure, and all maximum coma grades.

Survival among patients receiving liver transplants was slightly higher with NAC versus placebo but the difference was not statistically significant.

Adverse event rates were similar with NAC and placebo.

At the press briefing, Squires explained that NAC is presumed to work by scavenging reactive oxygen species, which are generated during inflammation and are at least partly responsible for tissue-damaging effects.

Some institutions, especially those overseas, had begun giving NAC to children with acute liver failure because of this presumed mechanism and because of its demonstrated effectiveness in adults.

That it appears not to help in pediatric acute liver failure sheds light both on the particular inflammatory patterns in the condition and also on the role of reactive oxygen species, he said.

"We're learning a lot more about the inflammatory cycle. Inflammation is not all bad," he said.

He said reactive oxygen molecules "can injure tissue but can also generate an environment for regeneration and healing."

Consequently, he suggested, NAC may actually interrupt those healthy aspects of inflammation in children with failing livers.

He said the same consortium that conducted the randomized trial was now embarking on a five-year study that, in part, would track inflammatory and immune markers in pediatric acute liver failure over time.

"Acute liver failure is dynamic and changes from day to day," he said. "It may well be that something that works today might not work tomorrow, depending on the footprint or pattern of inflammation. The focus will be on understanding the physiological dynamic of acute liver failure, with the idea that we could find targeted therapies that would work in a particular environment."

﻿The National Institute of Diabetes and Digestive and Kidney Diseases funded the trial.

Squires reported that he had no relevant financial interests. Some other investigators in the trial reported relationships with Vertex, Bristol-Myers Squibb, Schering-Plough, Salix, HepaLife, Roche, GlaxoSmithKline, Merck, Mead Johnson, Novartis, and Gilead.

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